3EYS

PFA1 Fab fragment complexed with pyro-Glu3-A-Beta (3-8)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 

wwPDB Validation   3D Report Full Report


This is version 2.1 of the entry. See complete history


Literature

Structures of Abeta-related peptide--monoclonal antibody complexes.

Gardberg, A.Dice, L.Pridgen, K.Ko, J.Patterson, P.Ou, S.Wetzel, R.Dealwis, C.

(2009) Biochemistry 48: 5210-5217

  • DOI: https://doi.org/10.1021/bi9001216
  • Primary Citation of Related Structures:  
    3EYS, 3EYU

  • PubMed Abstract: 

    Passive immunotherapy (PI) is being explored as a potential therapeutic against Alzheimer's disease. The most promising antibodies (Abs) used in PI target the EFRH motif of the Abeta N-terminus. The monoclonal anti-Abeta Ab PFA1 recognizes the EFRH epitope of Abeta. PFA1 has a high affinity for Abeta fibrils and protofibrils (0.1 nM), as well as good affinity for Abeta monomers (20 nM). However, PFA1 binds the toxic N-terminally modified pyroglutamate peptide pyro-Glu3-Abeta with a 77-fold loss in affinity compared to the WT Abeta(1-8). Furthermore, our earlier work illustrated PFA1's potential for cross-reactivity. The receptor tyrosine kinase Ror2, which plays a role in skeletal and bone formation, possesses the EFRH sequence. PFA1 Fab binds the Ror2(518-525) peptide sequence REEFRHEA with a 3-fold enhancement over WT Abeta(1-8). In this work, the crystal structures of the hybridoma-derived PFA1 Fab in complex with pyro-Glu3-Abeta peptide and with a cross-reacting peptide from Ror2 have been determined at resolutions of 1.95 and 2.7 A, respectively. As with wild-type Abeta, these peptides bind to the Fab via a combination of charge- and shape-complementarity, hydrogen-bonding, and hydrophobic interactions. Comparison of the structures of the four peptides Abeta(1-8), Grip1, pyro-Glu3-Abeta(3-8), and Ror2 in complex with PFA1 shows that the greatest conformational flexibility occurs at residues 2 to 3 and 8 of the peptide. These structures provide a molecular basis of the specificity tolerance of PFA1 and its ability to recognize Abeta N-terminal heterogeneity. The structures provide clues to improving mAb specificity and affinity for pyroglutamate Abeta.


  • Organizational Affiliation

    Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
If kappa light chainA [auth L]219Mus musculusMutation(s): 4 
Gene Names: Igk-C
UniProt
Find proteins for A2NHM3 (Mus musculus)
Explore A2NHM3 
Go to UniProtKB:  A2NHM3
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA2NHM3
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
PFA1 Fab Heavy ChainB [auth H]223Mus musculusMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence

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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
pyro-Glu3-A-Beta (3-8) peptideC [auth Q]6N/AMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth H]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Modified Residues  2 Unique
IDChains TypeFormula2D DiagramParent
YCM
Query on YCM
A [auth L]L-PEPTIDE LINKINGC5 H10 N2 O3 SCYS
PCA
Query on PCA
C [auth Q]L-PEPTIDE LINKINGC5 H7 N O3GLN
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.204 
  • R-Value Observed: 0.207 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.656α = 96.14
b = 42.677β = 93.83
c = 58.63γ = 91.73
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2009-05-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Non-polymer description, Version format compliance
  • Version 1.2: 2013-06-19
    Changes: Database references
  • Version 1.3: 2017-10-25
    Changes: Refinement description
  • Version 2.0: 2019-12-25
    Changes: Database references, Derived calculations, Polymer sequence
  • Version 2.1: 2023-12-27
    Changes: Data collection, Database references, Derived calculations